The present invention relates to devices configured to control the flow of fluid, and methods for making such devices.
Devices configured to deliver a fluid sample from a first location on the device to a second location, for example a test location provided with a reagent, are well-known. A particularly important application of such devices is in medical diagnostics, where a sample comprising a biological analyte is deposited on the device for flow to a test location for reaction with a reagent that tests for a disease or other clinical condition or parameter. Often the result of the test is indicated by a colour change at the test location. The device takes the form of a substrate that defines a fluid flow path or channel between the deposition site and the test site.
These devices are of great interest because the role of diagnostics and point-of-care (POC) testing is highly beneficial for early stage non-invasive clinical detection. POC testing provides an effective and rapid technique that excludes or minimises delay by providing a prompt exchange of vital information between the clinical care team and the patient, because the testing can be conducted at the point-of-care (which may be the patient's home, their general practitioner's clinic, or a hospital). The testing is facilitated through the use of uncomplicated, user-friendly and portable testing devices, and much effort has been directed towards producing diagnostic test-kits which are smaller, quicker and smarter, and importantly, cost-effective, which is a key requirement for enabling POC test procedures that may need to be performed repeatedly over large sample groups.
It has been recognised that microfluidic-based “lab-on-chip” (LOC) technology has considerable potential for medical diagnostics devices and systems [1]. Advantages of compact LOC devices include the use of smaller reagent volumes, faster reaction times and portability arising from the smaller device dimensions, and ease of manufacture. These devices were originally developed on platform substrates such as silicon and glass using clean-room based fabrication processes adapted from the semiconductor processing industry. Polydimethylsiloxane (PDMS), a low-cost polymer, has also been considered but has various limitations; this has led to a search for other substrate materials, which now include paper, cotton, thermoplastics and photo-curable polymers. In particular, paper is now considered as a highly suitable substrate for the fabrication of LOC-type devices [2, 3]. Of particular importance is the relatively low-tech nature of paper, which has almost all of the attributes that would help realise ‘low-cost’ POC diagnostic tests, particularly in the context of low-resourced locations in developing and third-world countries.
As a substrate material, paper is inexpensive, abundantly available in a range of different engineered forms that exhibit different properties, can be stored and easily transported, modified in terms of its liquid transport properties, and readily disposed of after use. Additionally, paper-based fabrication procedures themselves are relatively cheap, and paper as a technology has been in use for more than two thousand years, lending itself to routine low cost high volume production procedures. Finally, delivery of paper-based items is routinely available to everyone world-wide that has access to a postal service. Paper is currently implemented for analytical and clinical chemistry, and chromatographic tests are routinely performed for the detection of different chemical species. Two commonly known paper-based chromatographic clinical tests are the pregnancy test and the lateral flow-based urine dipsticks that can simultaneously detect blood sugar, pH and ketone [4]. Clinical tests that can yield quantitative information of a multiplexed nature (i.e. can perform a series of parallel tests) using a single test strip are very attractive, and microfluidic paper-based analytical devices (μPADs) are an ideal platform for this. These paper-based microfluidic devices have one or more flow channels that are designed to guide and transport an analyte fluid from a point of entry on the device to a reaction zone that has been pre-treated with specific reagents. Unlike glass, silicon and polymer substrates on which fluid channels have to be surface-relief structures, for paper-based device the channels are formed within and extend throughout the thickness of the paper. The walls that are required to delineate the individual channels to contain and guide the flow of liquids are made from hydrophobic materials integrated into the structure of the paper.
An early design for these structures relied on a cleanroom-based lithographic technique of exposure of a UV-sensitive polymer impregnated in a paper substrate through a custom-designed mask; this cross-linked the polymer to form the required pattern of fluid channels [5]. Lithography has also been proposed elsewhere [6, 7]. A development aimed at reducing costs arising from the lithographic procedure involved the use of a modified desktop plotter to dispense an ink composed of PDMS [8]. Other approaches include inkjet printer-based etching of paper impregnated with polystyrene [9], plasma-treatment through a metal mask of a paper impregnated with hydrophobic alkyl ketene dimer [10], paper-cutting using a computer-controlled X-Y knife plotter [11], printing of wax [12, 13], inkjet-printing [14, 15], flexographic printing [16], wax-screen printing [17], and laser-treatment of a paper with a hydrophobic coating [18]. Each of these techniques has its advantages and disadvantages. Lithography and plasma-treatment require expensive patterning masks or equipment and controlled laboratory conditions. The knife-plotting technique requires specialised or custom-modified patterning equipment, and other techniques may include undesirable post-processing procedures. Other issues are the limitation on achievable feature size resulting from lateral spreading of the hydrophobic material (for example with wax printing), the need for specialised chemicals and inks (for ink-jet printing), and the use of harsh chemical etchants.
Also, it is often desirable to control the fluid flow in the device so that the analyte flows along different channels at different speeds. The above fabrication techniques are often poorly suited to implement channel designs that offer the required flow rate control, and additional manufacturing steps can be needed to modify the channel network. Proposals for achieving flow rate control include using a circuitous or serpentine channel geometry to delay flow, and forming dissolvable barriers in the flow channels, for example made from sugar [19, 20, 21].
Hence, there is a requirement for improved microfluidic LOC-type devices, in particular devices in which the fluid flow speed can be modified or controlled, and improved methods for producing such devices.